Department of Medical Laboratory Studies, School of Health and Medical Care, Alexander Technological Educational Institute of Thessaloniki, Thessaloniki 57400, Greece.
Department of Pharmacy, School of Health, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
Curr Top Med Chem. 2019;19(4):246-263. doi: 10.2174/1568026619666190201152153.
Diabetes Mellitus (DM), is a metabolic disorder characterized by high blood glucose levels. The main types of diabetes mellitus are Diabetes mellitus type I, Diabetes mellitus type II, gestational diabetes and Diabetes of other etiology. Diabetes type II, the Non Insulin Dependent Type (NIDDM) is the most common type, characterized by the impairment in activation of the intracellular mechanism leading to the insertion and usage of glucose after interaction of insulin with its receptor, known as insulin resistance. Although, a number of drugs have been developed for the treatment of diabetes type II, their ability to reduce blood glucose levels is limited, while several side effects are also observed. Furthermore, none of the market drugs targets the enhancement of the action of the intracellular part of insulin receptor or recuperation of the glucose transport mechanism in GLUT4 dependent cells. The Protein Tyrosine Phosphatase (PTP1b) is the main enzyme involved in insulin receptor desensitization and has become a drug target for the treatment of Diabetes type II. Several PTP1b inhibitors have already been found, interacting with the binding site of the enzyme, surrounding the catalytic amino acid Cys215 and the neighboring area or with the allosteric site of the enzyme, placed at a distance of 20 Å from the active site, around Phe280. However, the research continues for finding more potent inhibitors with increased cell permeability and specificity.
The aim of this review is to show the attempts made in developing of Protein Tyrosine Phosphatase (PTP1b) inhibitors with high potency, selectivity and bioavailability and to sum up the indications for favorable structural characteristics of effective PTP1b inhibitors.
The methods used include a literature survey and the use of Protein Structure Databanks such as PuBMed Structure and RCSB and the tools they provide.
The research for finding PTP1b inhibitors started with the design of molecules mimicking the Tyrosine substrate of the enzyme. The study revealed that an aromatic ring connected to a polar group, which preferably enables hydrogen bond formation, is the minimum requirement for small inhibitors binding to the active site surrounding Cys215. Molecules bearing two hydrogen bond donor/acceptor (Hb d/a) groups at a distance of 8.5-11.5 Å may form more stable complexes, interacting simultaneously with a secondary area A2. Longer molecules with two Hb d/a groups at a distance of 17 Å or 19 Å may enable additional interactions with secondary sites (B and C) that confer stability as well as specificity. An aromatic ring linked to polar or Hb d/a moieties is also required for allosteric inhibitors. A lower distance between Hb d/a moieties, around 7.5 Å may favor allosteric interaction. Permanent inhibition of the enzyme by oxidation of the catalytic Cys215 has also been referred. Moreover, covalent modification of Cys121, placed near but not inside the catalytic pocket has been associated with permanent inhibition of the enzyme.
糖尿病（DM）是一种以高血糖为特征的代谢紊乱。主要类型的糖尿病包括 1 型糖尿病、2 型糖尿病、妊娠期糖尿病和其他病因的糖尿病。2 型糖尿病，即非胰岛素依赖型（NIDDM）是最常见的类型，其特征是胰岛素与其受体相互作用后，导致葡萄糖插入和使用的细胞内机制激活受损，称为胰岛素抵抗。尽管已经开发了许多药物来治疗 2 型糖尿病，但它们降低血糖水平的能力有限，同时也观察到一些副作用。此外，市场上的药物没有一种针对增强胰岛素受体细胞内部分的作用或恢复 GLUT4 依赖性细胞中的葡萄糖转运机制。蛋白酪氨酸磷酸酶（PTP1b）是胰岛素受体脱敏的主要酶，已成为治疗 2 型糖尿病的药物靶点。已经发现了几种 PTP1b 抑制剂，它们与酶的结合位点相互作用，围绕催化氨基酸 Cys215 及其邻近区域，或与酶的变构位点相互作用，该位点位于活性位点 20Å 处，围绕 Phe280。然而，研究仍在继续，以寻找具有更高细胞通透性和特异性的更有效抑制剂。
本综述的目的是展示开发高活性、选择性和生物利用度的蛋白酪氨酸磷酸酶（PTP1b）抑制剂的尝试，并总结有效 PTP1b 抑制剂的有利结构特征的指示。
使用的方法包括文献调查和使用 PuBMed Structure 和 RCSB 等蛋白质结构数据库以及它们提供的工具。
寻找 PTP1b 抑制剂的研究始于设计模仿酶的酪氨酸底物的分子。研究表明，连接到极性基团的芳环，最好能够形成氢键，是最小的要求，用于结合到围绕 Cys215 的活性位点的小分子抑制剂。带有两个氢键供体/受体（Hb d/a）基团的分子，距离为 8.5-11.5Å，可能形成更稳定的复合物，同时与 A2 区的次要区域相互作用。带有两个 Hb d/a 基团，距离为 17Å 或 19Å 的较长分子，可能与赋予稳定性和特异性的次要位点（B 和 C）形成额外的相互作用。连接到极性或 Hb d/a 部分的芳环也需要变构抑制剂。Hb d/a 部分之间的距离较小，约为 7.5Å，可能有利于变构相互作用。还提到了通过氧化催化 Cys215 来永久抑制酶的活性。此外，与催化口袋附近但不在内部的 Cys121 的共价修饰与酶的永久抑制有关。
